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US20060147388A1 - Pharmaceutical compositions for nasal delivery - Google Patents

Pharmaceutical compositions for nasal delivery Download PDF

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Publication number
US20060147388A1
US20060147388A1 US10/547,030 US54703004A US2006147388A1 US 20060147388 A1 US20060147388 A1 US 20060147388A1 US 54703004 A US54703004 A US 54703004A US 2006147388 A1 US2006147388 A1 US 2006147388A1
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Prior art keywords
excipient
formulation according
active material
particle size
formulation
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US10/547,030
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English (en)
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Franciscus Merkus
Peter Lambert
Gerald Adams
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Britannia Pharmaceuticals Ltd
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Individual
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Assigned to BRITANNIA PHARMACEUTICALS LIMITED reassignment BRITANNIA PHARMACEUTICALS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MERKUS, FRANCISCUS W.H., LAMBERT, PETER ALAN, ADAMS, GERALD
Publication of US20060147388A1 publication Critical patent/US20060147388A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates generally to formulations suitable for nasal delivery of pharmacologically and therapeutically active agents for systemic activity, in particular for nasal powders containing drugs such as apomorphine and dihydroergotamine and their salts.
  • administering drugs by the nasal route is advantageous in that the drug can be absorbed rapidly into the blood supply through the nasal tissue.
  • the drug can then travel systemically to target sites remote from the nasal cavity and provide a therapeutic effect at the target site.
  • Nasal delivery may also be used for active agents which act by inducing a localized therapeutic response within the nasal tissue e.g. an immunological response to reduce localized allergic reactions such as rhinitis.
  • U.S. Pat. No. 5,756,483 issued to Merkus which is hereby incorporated by reference, discloses the intranasal delivery of a variety of compositions, including apomorphine and dihydroergotamine, in powder form, for example in combination with a cyclodextrin and/or a disaccharide and/or a polysaccharide and/or a sugar alcohol, for treating several diseases and/or disease symptoms.
  • the drug is usually dispersed in an aqueous vehicle to facilitate delivery.
  • a liquid vehicle is used in which the active agent is dissolved and delivered to the nasal cavity as an aqueous nasal spray or via a metered propellant system.
  • liquid formulations are simply delivered, they have a number of limitations.
  • the dose of poorly water soluble drugs that can be delivered is limited, compounds may have limited stability in solution (requiring the inclusion of stabilizing agents) and generally preservatives are required to maintain microbiological quality. Preservatives may cause toxic or allergic reactions and/or disturb the mucociliary clearance of the nose.
  • the use of powder formulations can provide advantages in these areas as the deliverable dose can be less limited, powders are inherently stable and there is no requirement for preservatives.
  • a suitable mean particle size is in the range of from 5 to 150 ⁇ m. This is because particles of a size less than 5 ⁇ m may be deposited partly in the lung (N. Mygind, Nasal Allergy, 2nd Edition 1981, Blackwell Scientific Publications, London, pages 45-47). On the other hand, particles having a size greater than about 150 ⁇ m may induce the sneeze reflex causing ejection of the entire dose from the nasal cavity and are too large to be dissolved quickly in the aqueous mucosal layer in the nose resulting in removal by nasal mucociliary clearance (Marttin et al. Nasal mucociliary clearance as a factor in nasal drug delivery, Adv. Drug Deliv. Reviews 19, 1998, 13-38).
  • a powder sample will usually have a range of particle sizes distributed around a mean particle size.
  • the mean particle size to be in the range of from 5 to 150 ⁇ m but also the amounts of particles with a size less than 5 ⁇ m or greater than 150 ⁇ m need to be minimised.
  • the particle size distribution curve needs to be narrow such that the particle size distribution is not polydisperse.
  • a crystalline matrix provides a more straightforward system for freeze drying since crystalline materials are simple to assay, present few problems during processing and can provide a very shelf-stable product. For respiratory purposes they provide a dried matrix where individual particles absorb only a finite amount of moisture when exposed to a damp atmosphere and the particle will remain unchanged during storage. In general therefore a crystalline matrix is preferred for freeze-drying. However, when a freeze-dried product is intended for nasal application, the particles should be such that the particle size is optimized for efficient nasal absorption. By variation of the freezing and drying conditions, particle size can be adjusted to a limited extent. However crystalline matrices often display a size distribution which exhibits a pronounced low particle size tail defined as finings, which cannot be prevented totally by altering freezing or drying conditions. These finings may induce undesirable effects such as lung deposition of very small particles.
  • the active component may be amorphous or may require stabilization of its molecular structure by including amorphous protectants in the formulation.
  • a further problem is that production of particles by milling tends to increase the amount of finings (particles having a size less than 10 ⁇ m) which is unacceptable for the reasons given above.
  • the present invention is based on the surprising finding that by selection of components with a specific crystalline/amorphous balance, powder formulations of active materials and excipients of suitable particle size for nasal delivery can be directly obtained by freeze drying without the need for milling and without containing the pronounced low particles defined as finings. Such powders retain free-flowing properties on storage, are physically and chemically stable and are readily soluble.
  • the present invention provides a powdered pharmaceutical formulation for nasal delivery which is a freeze-dried blend of active material(s) and excipient(s) containing:
  • one formulation of the invention may contain:
  • composition of the invention may contain:
  • a formulation of the invention may contain:
  • an additive/stabilizer for the active material such as an antioxidant
  • the freeze dried blend of excipient(s) and active material(s) according to the invention is generally in composition identical to that of an aqueous solution of excipient(s) and active material(s). Therefore an average particle of a formulation according to the invention will contain active material and excipient in the same percentage amounts as their percentages in the original solution.
  • crystalline/amorphous character of active material(s) and excipient(s) intended for freeze-drying in accordance with this invention may be assessed as three groups:
  • Active material(s) and excipient(s) which are crystalline and which persist in this form throughout freeze drying to provide a dried, crystalline matrix.
  • the excipient(s) may be defined as crystalline and may be selected from a eutectic salt (such as sodium chloride, potassium chloride), certain amino acids (such as glycine), certain sugar alcohols (such as mannitol and sorbitol), and other organic molecules.
  • Active material(s) and excipient(s) which are crystalline but which may be induced into a non-crystalline or amorphous state by freezing and once in this state remain amorphous throughout subsequent drying, final finishing, storage and distribution.
  • examples include certain amino acids (such as glutamine or serine), a monosaccharide (such as glucose), a disaccharide (such as sucrose, trehalose, lactose), a trisaccharide (such as raffinose), a polysaccharide, certain polyethylene glycols (such as polyethylene glycols having a molecular weight of about 6000), certain polypeptides (such as a polyamino acids) and/or polymers (such as poly-d-lactic acid).
  • amino acids such as glutamine or serine
  • a monosaccharide such as glucose
  • a disaccharide such as sucrose, trehalose, lactose
  • a trisaccharide such as raffinose
  • Active material(s) and/or excipient(s) which are non-crystalline (amorphous) and which are maintained in the amorphous state throughout subsequent drying, dispensing and final finishing, storage and distribution.
  • examples include certain saccharides (such as amorphous lactose), certain polyethylene glycols (such as polyethylene glycols having a molecular weight up to 1000), a polyglycan, a polysaccharide (such as a dextran), a cyclodextrin, povidone, micro-fine cellulose, certain polymers (such as potato starch) and a protein.
  • the active component or components suitable for use in this invention include, for example:
  • active component(s) may be incorporated into a single formulation to provide a more effective product.
  • the active component(s) may be augmented by adding a simple or complex compound which may not be active itself but which may potentiate the effects of the active component(s) or act as an adjuvant.
  • the formulation may also include an active component stabiliser.
  • the active material is preferably apomorphine and/or dihydroergotamine and/or a salt thereof.
  • a suitable salt is apomorphine hydrochloride and/or one or more other water soluble pharmaceutically acceptable salts.
  • a suitable salt is dihydroergotamine mesylate and/or tartrate and/or one or more other water soluble pharmaceutically acceptable salts.
  • An excipient to be used in a formulation of this invention must satisfy the crystalline/amorphous parameter given above, and preferably should satisfy one or more of the following parameters:
  • Excipient(s) that may be used, subject to the required crystalline/amorphous balance, include a saccharide, a polysaccharide and/or a sugar alcohol.
  • cyclodextrin refers to a cyclic oligosaccharide, such as alpha-, beta- and gamma-cyclodextrin and/or a derivative therof, such as methylated beta-cyclodextrin.
  • saccharide includes a monosaccharide (such as glucose), a disaccharide (such as lactose, maltose, trehalose, sucrose, and/or saccharose) and a polysaccharide (such as a dextran).
  • a monosaccharide such as glucose
  • a disaccharide such as lactose, maltose, trehalose, sucrose, and/or saccharose
  • a polysaccharide such as a dextran
  • sugar alcohol refers to a saccharide polyol such as mannitol, sorbitol, inositol and/or xylitol.
  • the nasal powder formulation according to the invention have the advantage that no preservatives (i.e. bactericides or fungicides) are necessary. Preservatives are known to decrease the ciliary movement, which may be harmful in chronic nasal medication (Hermens W. A. J. J. and Merkus F. W. H. M., Pharm. Res. 1987; 4: 445-449).
  • the formulation according to the invention can be administered using a nasal insufflator or a passive device.
  • the formulation is placed in a capsule which is set in an inhalation or insufflation device.
  • a needle is penetrated through the capsule to make pores at the top and the bottom of the capsule and air is drawn in by inhalation or blown through the device to force out the powder particles into the patient's nose.
  • the formulation can also be administered in a jet-spray of an inert gas or suspended in liquid organic fluids.
  • the required amount for a nasal administration of a nasal formulation according to the invention may be, for example, between 1 and 50 mg, typically 1 to 20 mg, for example administered as about 5 to 20 mg per nostril.
  • a formulation according to the invention for use in therapeutic treatment of a human or animal body by nasal administration.
  • the formulation is preferably for use in treatment of migraine and/or Parkinson's disease and/or sexual dysfunction by nasal administration.
  • a formulation according to the invention in the manufacture of a medicament for use in therapeutic treatment of a human or animal body by nasal administration.
  • the medicament is for use in treatment of migraine and/or Parkinson's disease and/or sexual dysfunction by nasal administration.
  • a method of medical treatment which method comprises supplying to a human or animal (preferably mammal) patient a therapeutically effective amount of a formulation according to the invention.
  • the formulation is preferably supplied to the patient by nasal administration.
  • the method is preferably for the treatment of migraine and/or Parkinson's disease and/or sexual dysfunction in a human patient.
  • the formulation of the present invention is generally prepared by freeze-drying.
  • the active component(s) and excipient(s) should be compatible with the drying process and should provide a bulk within the processing container to prevent the migration of drying product during processing (ablation). It has been established that by working within the crystalline/amorphous parameter defined above, it is possible to predictably obtain a resultant dried powder which exhibits a particle size suitable for comfortable retention and a fast dissolution of the active material in the nasal mucosa, followed by absorption into the systemic circulation.
  • the dried formulation according to the invention comprises particles which remain stable and uniform throughout processing, final finishing, storage and distribution.
  • the formulation is shelf-stable and free-flowing, presents no problems when dispensed into its final container and is simple to administer by the patient.
  • the ratio and persistence of the amorphous and crystalline contents of the formulation according to the invention may be determined for compliance with crystalline/amorphous parameter defined above by a thermal analysis technique including differential scanning calorimetry.
  • the particle size distribution pattern of the formulation may be defined by particle size characterisation using a laser diffraction technique with, for example, Mastersizer instrumentation from Malvern Instruments. This laser diffraction powder characterization technique may be carried out directly on a dry powder sample of the formulation (dry analysis) or on a sample of the formulation suspended in a solvent in which the formulation is not soluble (wet analysis). It is necessary to ensure that each sample analysed is fully de-aggregated at the time of characterization and this is best achieved using the wet analysis method.
  • de-aggregation of particle agglomerates can be achieved by the use of dispersing agents, surfactants and/or sonication of the sample prior to analysis and maintained by stirring or recirculation of the sample during analysis.
  • de-aggregation of the sample can be verified visually under a microscope.
  • the formulation according to the invention preferably has one or more of the following properties:
  • the particle size, as measured by laser diffraction, under which 10% by volume of the particles are distributed is at least 5 ⁇ m, preferably at least 6 ⁇ m, more preferably at least 9 ⁇ m, most preferably at least 10 ⁇ m, particularly preferably at least 15 ⁇ m.
  • the particle size, as measured by laser diffraction, under which 90% by volume of the particles is distributed (D(v,0.9)) is preferably at most 150 ⁇ m, more preferably at most 125 ⁇ m, most preferably at most 100 ⁇ m, particularly preferably at most 80 ⁇ m, more particularly preferably 50 ⁇ m, especially 45 ⁇ m.
  • the particle size distribution (calculated as the difference between D(v,0.9), and D(v,0.1)) is preferably at most 140 ⁇ m, more preferably at most 110 ⁇ m, most preferably 50 ⁇ m, particularly preferably 40 ⁇ m.
  • freezing conditions should preferably be selected to provide:
  • Differential scanning calorimetry, differential thermal analysis and resistance analysis may be used to define optimum freezing conditions. From such analysis, we have found it desirable that the product should be frozen at a slow rate or a heat annealing cycle applied to induce or maintain the correct matrix composition. For example a freezing rate of about 0.1 to 0.5° C. per minute and a heat annealing cycle comprising, for example: cool product to ⁇ 45° C. at 0.1-1.0° C. per minute; hold 2 hours, warm to ⁇ 15° C., hold 2 hours, re-cool to ⁇ 45° C., hold 2 hours before drying; have been used. These values may be used for guidance, but will vary depending on the formulation of the active material and limitations introduced by the apparatus and other component(s) used in freeze-drying.
  • a suitable drying cycle includes heating directly to 5° C. for main drying, increased chamber pressure to 150 mTorr to facilitate heat input and increased final drying temperature to 20° C.
  • Variations on this cycle, designed for specific product/process optimisation include a cycle where shelf temperature was raised to 15° C. for the initial phase of main (primary) drying and then progressively reduced to 5° C. for the remainder of main (primary) drying with chamber pressure increased up to 300 mTorr to facilitate heat input into product followed by increased shelf temperature to 25° C. for final (secondary) drying.
  • FIG. 1 shows a graph showing the dissolution rate of two different formulations of apomorphine nasal powder
  • FIG. 2 shows a graph plotting the apomorphine plasma concentration against time for three different comparative doses of apomorphine nasal powder, not produced according to the invention.
  • FIG. 3 shows a graph plotting the apomorphine plasma concentration against time for four different doses of apomorphine nasal powder prepared according to the invention.
  • All the above formulations contain an amount of the active ingredient appropriate for a therapeutic dose on administration of 5-20 mg of powder per nostril.
  • each sample produced by freeze drying was then measured by using a Malvern Instruments Mastersizer laser diffraction machine having a 300 mm range lens, a beam length of 14.30 mm and sampler MS7. Hexane was used as the solvent, the wetter was Span 85 and each sample was sonicated for 1 minute before being measured.
  • FIG. 1 describes the dissolution rate of two different formulations of apomorphine nasal powder (comparative example 4 & example 20).
  • Comparative Example 4 is not according to this invention and was prepared by the mixing of the components of the formulation without freeze drying.
  • the formulation comprised the following components:
  • Example 20 is a formulation in accordance with this invention prepared according to method example 1 and comprised the following components:
  • This model was chosen as over a period of 10-20 minutes the powder is exposed to 1-2 mL of dissolution media. This correlates well with the residence time of particles deposited in the nasal cavity prior to removal by mucociliary clearance and the order of magnitude of volume of fluid typically present in a healthy nose.
  • the dissolution of the sample is measured at specified intervals and the results in FIG. 1 are a mean of duplicate determinations.
  • Three formulations not according to this invention were prepared by simple mixing of the components of the formulation without freeze drying.
  • the three formulations comprised the following components:
  • examples 21 & 22 were administered to 6 healthy, male subjects as single 20 mg aliquots in one nostril (facilitating delivery of apomorphine HCl doses of 0.5 mg and 2 mg respectively) and as 40 mg aliquots comprising a single 20 mg aliquot in each nostril (facilitating delivery of apomorphine HCl doses of 1 mg and 4 mg respectively).
  • Each dose was administered on a separate day in order of ascending dose and blood samples were collected at regular intervals over a 6 hour period following dosing. Blood samples were measured using validated proprietary LC/MS-MS methodology at Chemical Synthesis Services, 38 Castleroe Road, Coleraine, Northern Ireland.
  • the PK profiles in FIGS. 2 and 3 show that the formulations according to the invention are absorbed much more efficiently and deliver much higher blood levels (almost twice as high) than those outside of the invention. This performance is clearly advantageous and shows that the nasal administration route is viable with the formulations according to the invention.
  • Apomorphine is currently available as an aqueous solution for subcutaneous injection or infusion. It is indicated in Parkinson's disease (PD) for the treatment of motor fluctuations refractory to other medications. These motor fluctuations (otherwise referred to as the ‘on/off’phenomenon’) are characterised by ‘off’ periods during which patients experience profound episodes of one or more of bradykinesia/akinesia, tremor and rigidity.
  • intranasal apomorphine powder (5 mg) alleviated the ‘off’ episode.
  • the mean latency of response after intra-nasal dosing was 18 minutes (range 5-30 minutes) compared to 27 minutes (range 14-61 minutes) after subcutaneous dosing (2-5 mg).
  • the mean duration of response after intra-nasal dosing was 93 minutes (range 19-153 minutes) compared to 62 minutes (range 43-96 minutes) after subcutaneous dosing. No serious local or systemic reactions were demonstrated after intra-nasal apomorphine dosing.

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US10/547,030 2003-02-28 2004-03-01 Pharmaceutical compositions for nasal delivery Abandoned US20060147388A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0304636.4A GB0304636D0 (en) 2003-02-28 2003-02-28 Pharmaceutical composition for nasal delivery
GB0304636.4 2003-02-28
PCT/GB2004/000846 WO2004075824A2 (fr) 2003-02-28 2004-03-01 Compositions pharmaceutiques pour administration nasale

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US (1) US20060147388A1 (fr)
EP (2) EP1596863A2 (fr)
JP (2) JP2006519219A (fr)
CN (1) CN1802158A (fr)
AU (2) AU2004216458B2 (fr)
CA (1) CA2516459A1 (fr)
GB (1) GB0304636D0 (fr)
WO (1) WO2004075824A2 (fr)

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US20110086875A1 (en) * 2007-08-06 2011-04-14 Britannia Pharmaceuticals Limited Powdered Medicament for Nasal Delivery of Ascorbic Acid for Reducing Apomorphine Induced Toxicity to Ciliated Tissue
WO2015044782A3 (fr) * 2013-09-24 2015-06-11 Shin Nippon Biomedical Laboratories, Ltd. Dhe intranasale pour le traitement de maux de tête
GB2581431A (en) * 2018-12-11 2020-08-19 Satsuma Pharmaceuticals Inc Compositions, devices, and methods for treating or preventing headaches
US10758532B2 (en) 2018-12-11 2020-09-01 Satsuma Pharmaceuticals, Inc. Compositions, devices, and methods for treating or preventing headaches
US10792253B2 (en) * 2016-08-05 2020-10-06 Shin Nippon Biomedical Laboratories, Ltd. Pharmaceutical compositions
WO2022009248A1 (fr) * 2020-07-07 2022-01-13 Jordan University Of Science And Technology Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant
US12115222B2 (en) 2023-01-23 2024-10-15 Villya LLC Compositions and methods for improving the solubility of erectile dysfunction therapeutics
US12390417B2 (en) 2020-08-12 2025-08-19 Villya LLC Praziquantel formulations

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ES2538082T3 (es) 2007-02-11 2015-06-17 Map Pharmaceuticals Inc Método de administración terapéutica de DHE para permitir el rápido alivio de migraña mientras que se minimiza el perfil de efectos secundarios
WO2009040595A1 (fr) * 2007-09-28 2009-04-02 Wockhardt Research Centre Composition pharmaceutique à multiples doses d'un analgésique pour administration nasale
JP5450481B2 (ja) 2010-03-17 2014-03-26 株式会社豊田中央研究所 アンテナ
HK1216250A1 (zh) 2012-12-21 2016-10-28 Map Pharmaceuticals, Inc. 8'-羟基-二氢麦角胺化合物及组合物
US20160296463A1 (en) * 2013-11-11 2016-10-13 Impax Laboratories, Inc. Rapidly disintegrating formulations and methods thereof
WO2016081466A1 (fr) * 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Administration sublinguale de riluzole
AU2018295505A1 (en) * 2017-07-02 2020-01-23 Dr. Reddy's Laboratories Ltd. Nasal dosage forms of dihydroergotamine
BR112020013750A8 (pt) * 2018-01-05 2022-10-18 Impel Neuropharma Inc Dispensação intranasal de olanzapina por dispositivo olfativo de precisão
WO2020261619A1 (fr) * 2019-06-26 2020-12-30 株式会社リコー Composition pharmaceutique
AU2023388890A1 (en) * 2022-12-07 2025-06-26 Daocheng Zhu Formulation and use of a fusion protein

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EP2258368A3 (fr) 2012-08-01
AU2004216458B2 (en) 2010-03-25
AU2004216458A1 (en) 2004-09-10
CN1802158A (zh) 2006-07-12
WO2004075824A3 (fr) 2004-10-21
EP1596863A2 (fr) 2005-11-23
WO2004075824A8 (fr) 2005-09-09
JP2011052021A (ja) 2011-03-17
EP2258368A2 (fr) 2010-12-08
JP2006519219A (ja) 2006-08-24
WO2004075824A2 (fr) 2004-09-10
CA2516459A1 (fr) 2004-09-10
AU2010202623A1 (en) 2010-07-15

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